Addressing threats to health care's core values, especially those stemming from concentration and abuse of power. Advocating for accountability, integrity, transparency, honesty and ethics in leadership and governance of health care.

Monday, June 23, 2008

The Clinical Trials "Torture Economy"

Two recent commentaries in major medical journals on the same topic failed to get the recognition they deserved. Both were about exploitation of the poor in clinical research, usually in Phase I drug trials conducted by contract research organizations (CROs), supervised by for-profit institutional review boards (IRBs), and both paid by pharmaceutical, biotechnology or device companies.

The first article was by Carl Elliott and Roberto Abadie. [ Elliott C, Abadie R. Exploiting a research underclass in phase I clinical trials. N Engl J Med 2008; 358: 2316-7. Link here.] Per Elliott and Abadie, the context is:

Over the past decade, clinical trials have moved from universities to private testing sites, the pressure to recruit subjects quickly has intensified, and ethical oversight has been outsourced to for-profit institutional review boards (IRBs). Payment to subjects has escalated, creating 'shadow economies' in cities throughout North America and elsewhere.

The authors then cited several misadventures that we have discussed on Health Care Renewal: the trials by SFBC International (now PharmaNet Development Group) in Miami that enrolled immigrants, often undocumented, under questionable circumstances and in Montreal that resulted in the transmission of active tuberculosis (see post here and links backward); and the trial by Parexel International in London that put most of the subjects in intensive care (see post here, with links backward).

Elliott and Abadie concluded "there are good reasons to believe that poor subjects are being exploited," and cited several justifications for this belief:

"Poor people are less likely than wealthier ones to get access to the drugs in question." This "appears to contravene article 19 of the Declaration of Helsinki, which states that medical research is ethically justified only if there is a reasonable chance that the population in which it is conducted will benefit from the results."

"The U.S. oversight system is not well equipped to monitor a highly competitive, market-based, multinational research industry." The Office for Human Research Protection "has no jurisdiction over privately sponsored studies," the US Food and Drug Administration (FDA) has insufficient funds to monitor all but a tiny minority of trials. The institutional review boards (IRBs) that are supposed to supervise trials are ill-equipped to protect against the sort of abuses that are likely. Furthermore, for-profit IRBs that are dependent on research sponsors for repeat business may be loathe to upset the apple-cart.

"Most sponsors apparently do not provide free care or treatment when subjects are injured."

Elliott and Abadie observed that most subjects in such trials see their participation as a job, rather than as a voluntary activity to promote science and human welfare. As the authors point out, if so, it is a poorly paid, risky job with few benefits and protections. Their conclusion is troubling,

The result is what one Philadelphia trial subject describes as 'a mild torture economy.' 'You are not being paid to do something,' he explains. 'You are being paid to endure.'

The only addition I can make is not only does the treatment of some patients in such trials appear inhumane, it amounts to bad science. Results from "professional trial subjects," who are likely to conceal characteristics which might have excluded them from this line of work, who may undergo one trial while still recovering from the effects of a previous, undisclosed trial, and who may be prone not to follow study protocols likely will not generalize to the patients who might actually be candidates for the drugs and devices assessed.

An editorial in the American Journal of Medicine was based on an article by Carl Elliott on the same topic published in the New Yorker. [Alpert JS. Dealing with ethical conflicts in clinical research. Am J Med 2008; 121: 457. Link here.]

His main conclusions were:

The ethical failure of such activities is obvious. The Nuremburg and Helsinki codes, developed following the human experimental atrocities of World War II, strongly advocate for voluntary participation on the part of research subjects. The substantial sums of money paid to the human 'guinea pigs' described by Elliott clearly obfuscate any volunteerism on the part of the individuals involved in these clinical experiments.

Lives saved and disease suffering lessened at the expense of individuals who are lured and perhaps even coerced into clinical trial participation cannot be allowed to continue in an open and equitable democracy. Clearly, the article by Elliott should be widely disseminated among academic and community physicians and governmental authorities. The topic should be openly discussed leading to corrective actions. Steps must be taken in the near future to protect the lives and the civil rights of individuals participating in clinical research studies.

Despite this call, I found no news coverage, and so far, no public discussion of any kind of the issues raised by these articles.

I hope that the charges that many current trials violate international ethical standards might get some peoples' attention, and maybe even inspire some action. I am not optimistic that anything will be done too hastily. After all, a lot of people are benefiting financially by the current scandalous status quo. They will not give up their ill-gotten gains gracefully. But this "mild torture economy" signals the approaching moral bankruptcy of our current health care system.

An anecdotal data point re: CRO's - they would not even talk to me, a medical informatics specialist.

"There is nothing in your CV of value to a CRO" said the (non-MD) VP of data and biometrics at a local CRO, here in suburban Philadelphia, in the heart of Merck-land when I was seeking re-employment after Merck's mass reduction in force in late 2003.

You do not need to be a doctor to question a drug company's use, or abuse, of test subjects. The June 19, 2008, WSJ highlights Sanofi's resubmission to the FDA of the drug dronedarone, brand name Multaq for heart issues. In the quick and dirty world of business I would say this drug has twice the death potential (8.1 v 3.8) as not taking any drug and the earlier trial, Andromeda, was halted due to the high incident of death in test subjects. Only now, five years later, are the study results being published.

How much of this information has been given to the new test subjects? How much of the old data has been "massaged" to produce the desired results? With approval: How many patients will die or will the entire potential use population of 2.2M Americans and 4.5M EU residents become the new test subjects?

Sanofi's feels this could become a new blockbuster with sales of over $1B. Telling is the quote from Paul Chew of Sanofi's R&D "I would say a majority of patients would be eligible for this treatment." I am sure this is the message the drug reps will carry to the doctors.

If I were to rate the corruptive tactics performed by big pharmaceutical companies, the intentional strategy of implementing fabricated and unreliable results of clinical trials performed by others, yet sponsored by a pharmaceutical company, would be at the top of the list. By this atrophy of the scientific method absent of authenticity, harm and damage is possibly done to the health of the public. Most would agree that the science of research should be sound and sterile that is completely free of interference. However, it appears, money and increased profits can be a catalyst for reckless disregard for human health that is largely unregulated. This is particularly a factor on post-marketing studies of various pharmaceutical companies.Decades ago, clinical trials were conducted at academic settings that focused on the acquisition of knowledge and the completely objective discoveries of meds. Then, in 1980, the Bayh-Dole Act was created, which allowed for such places to profit off of their discoveries that were performed for pharmaceutical companies in the past. This resulted in the creation of for-profit research trial sites, called Contract Research Organizations that are often composed of community patient care clinics. Because of this structure, investigators of these trials are likely void of necessary research experience or quality regarding their research purpose and ability to ensure its sterility. These quite numerous CROS are for- profit, with some CROs making billions of dollars a year. The trials conducted at such places are sponsored by pharmaceutical companies that control and manipulate all aspects of the trial being conducted involving their med being studied in the trial. Etiology for their deception regarding this manipulation is because the pharmaceutical company that sponsors such a trial is basically creating a marketing tool for the studied drug of thiers. This coercion is done by various methods of deception in subtle and tacit methods. As a result, research in this manner ensures favorable results of the sponsor’s medication. Their activities are again believed to be absent of true or applied regulation, and therefore have the autonomy to create whatever they want to benefit what may be a collusive relationship between the site and the sponsor.Further disturbing is that once the creation of the trials is completed, the research paper is often composed with specific directions by the sponsor to writers known as ghostwriters. These people are not identified and acknowledged by the sponsor, and may not be trained in clinical research overall, as they are simply freelance writers, as one does not need research training or certification in order to perform this function. Rarely do trial ghostwriters question their instructions about their assignment, which is clearly deceptive and undocumented by the sponsor. Also, these hired mystery writers are known to make about 100 grand a year. This activity removes accountability and authenticity of the possibly fabricated clinical trial even further. The corruptive act is finally completed by the sponsor hiring an author to have their name be placed on the trial, while this hired author likely had absolutely no involvement with the trial, or even reviewing the trial is not asked by the hired author. To have the trial published, the sponsor has been known to pay a journal, and the sponsor bribes the journal in a few ways, such as the sponsor purchasing from a selected journal thousands of reprints of their study from the journal, for example. Again, how often this process is performed is unknown, yet frequent enough to create hundreds of such false writers mentioned earlier and progressively growing research sites to receive the support the pharmaceutical industry. So benefits of meds studied in such a malicious way potentially can harm patients and their treatment options along with clear safety risks. The purchased reprints bought by the sponsor of the study are distributed to the sponsor’s sales force to share the content with prescribers, with the sales force completely unaware about this manipulation. As a bonus, the sponsor may pay this journal to advertise their products to be placed in this journal as well.Such misconduct discussed so far impedes research and the scientific method with frightening ethical and harmful concerns.. If so, our health care treatment options with meds are now undetermined in large part due to such corruptive situations, as well as the absence of objectivity that has been intentionally eliminated with trials produced in this way. Trust in the scientific method in this type of activity illustrated in this article is absent. More now than ever, meds are removed from the market are given black box warnings. Now I understand why this may be occurring.Transparency and disclosure needs to happen with the pharmaceutical industry for reasons such as this as well as many others, in order to correct what we have historically relied upon for conclusive proof, which is the scientific method. More importantly, research should not be conducted in a way that the sponsor can interfere in such ways described in this article, which would require independent clinical trial sites with no involvement with the drug maker. And clearly, regulation has to be enforced not selectively, but in a complete fashion regarding such matters. Public awareness would be a catalyst for this to occur, after initially experiencing a state of total disbelief that such operations actually are conducted by such people, of course. We can no longer be dependent on others for our optimal health. Knowledge is power, and is also possibly a lifesaver.

“Ethics and Science need to shake hands.” ……. Richard Cabot

Dan Abshear

Author’s note: What has been written was based upon information and belief.

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